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10/7/2015
Signal Transduction Pathways
Chapter 13, Stryer Short Course
Signal Transduction
• Signal from exterior of cell must affect interior of cell
• Through the membrane
• Amplification of signal
• Ability to turn off
A few pathways…
• Example pathways
– ‐adrenergic receptor (epinephrine)
– ‐adrenergic receptor (epinephrine)
– Epidermal growth factor receptor
– Insulin receptor
• Same hormone can elicit different responses in different tissues
• Cross‐talk: different hormones elicit same response (fine tuning)
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Terms for Signal Transduction Mechanisms
• Ligand (primary message)
• Receptor
• Transducer
• Effector
• Second messenger
• Target proteins/DNA
1. ‐adrenergic receptor
G‐Protein Signaling Pathways
• Use ‐adrenergic receptor as example of G‐
Protein Coupled Receptor (GPCR)
• 7‐transmembrane helix (7‐TM) receptor
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G‐Protein Coupled
• Ligand binding causes G‐protein to associate with receptor (figure not quite right)
• Three subunits, lipid anchored
–  binds GDP
–  tightly associated
• Binding causes GDP release, allows GTP binding
G‐Protein Deactivation
• Turn off: Slow GTP hydrolysis
– Subunits reassemble to inactive form until they can bind receptor again
Second Messenger
• G‐protein activates Adenylate cyclase • Catalyzes formation of cAMP
• Amplification
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Function of cAMP
• cAMP acts as second messenger to activate Protein Kinase A (allosteric activator)
• Regulatory and catalytic subunits
PKA: Phosphorylation
• Common activation/
deactivation strategy
• Changes protein conformation drastically
• Covalent modification
• Activates enzyme that releases sugar stored in muscle
Summary
• Exercise: use basic guide to explain mechanism of epinephrine effect on sugar release in muscle
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Turning Off Pathway
• Can turn it off at any point
– Receptor?
– G‐protein?
– Second messenger?
– Phosphorylated enzyme?
2. ‐adrenergic receptor
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Epinephrine
7‐TM helix
G‐protein
Phospholipase C
DAG & IP3
Ca+2
Protein Kinase C
Phosphinositol Pathway
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3. Epidermal Growth Factor
• Receptor Tyrosine Kinases
– Dimerization and autophosphorylation
– Adaptor proteins
– G‐protein: Ras
– Kinase cascade
Insulin Receptor
• Receptor Tyrosine Kinases
– Dimerization and autophosphorylation
– Adaptor proteins
– Phosphoinositide kinase
– PIP3
– Kinase cascade
Summary
Ligand
‐adrenergic
‐adrenergic
EGF
Insulin
epinephrine
epinephrine
EDF
Insulin
Receptor
7‐TM helix
7‐TM helix
Tyr Kinase
Tyr Kinase
Transducer
G‐protein
G‐protein
Ras (G‐protein)
PIP2 kinase
Second messenger
cAMP
PIP2 , DAG (Ca+2)
(various)
PIP3
Effector
PKA
PKC
(Various pecific
protein kinases)
PKB (Akt)
Example effect
Increase blood Glucose pressure
release in liver
Cell growth
Increase
glucose uptake from blood
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Pathology
• Cholera
– Covalent modification of a G‐protein
– Constitutively active
– Opens chloride channel; leads to severe diarrhea
• Whooping cough
– Toxin turns off an inhibitory G‐protein
– Adenylate cyclase remains active
Cancer
• Proto‐oncogenes and oncogenes
• Ras targets nuclear proteins; Key signal in cell growth
• Mutant Ras proteins have been found to be associated with various types of cancer. What is the effect on a cell if the mutant Ras is able to bind GTP but is unable to hydrolyze it?
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